This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Chemotherapy and radiation therapy heavily damage hematopoietic stem cells (which must be protected throughout life). Approaches for improving efficiency of these therapies therefore should include measures to either increase tumor sensitivity, and/or reduce toxicity to these critical stem cells. The latter approach requires a careful dissection of survival signalling pathways in hematopoietic stem and progenitor cells. We previously discovered how Slug, a member of the Slug/Snail family of zinc-finger transcriptional repressors, allows myeloid progenitor cells to evade the lethal effects of genotoxic agents. In myeloid progenitors, Slug protects mice from gamma radiation-induced death in a cell autonomous manner by antagonizing p53's upregulation of Puma, a BH3-only proapoptotic factor of the mitochondria-dependent apoptosis pathway. Our findings further implicate Slug as a candidate key antiapoptotic factor in hematopoietic stem cells, and supporting data indicate that Slug is expressed by hematopoietic stem cells. It remains to be established whether Slug protects these essential cells from death due to DNA damage, and mechanistically how. To address these questions, we proposed two specific aims: Aim 1: Investigate the extent to which endogenous Slug protects hematopoietic stem cells from the lethal effects of gamma-radiation induced DNA damage Aim 2: Investigate whether enforced expression of Slug enhances protection of hematopoietic stem cells against lethal dose irradiation